5alpha-hydroxy-6beta-aminosteroids of the androstane series



United States Patent 3,156,710 Su-HYDROXY-fi-AMINOSTEROIDS OF THE ANDROSTANE SERIES Kanzo Sasalri, Osaka, Japan, assignor to Shionogi 8; Co., Ltd, Osaka, Japan No Drawing. Filed July 11, 1963, Ser. No. 294,237 5 Claims. (Cl. 260-349) The present invention relates to a process for preparing 5u-hydroxy-6fiaminosteroids of the androstane series. More particularly, it relates to a process for converting a 5a,6rx-epoxysteroid of the androstane series into the corresponding 5ot-hydroxy-6,8-aminosteroid of the androstane series substantially by two steps, i.e. ring opening and reduction.

Hitherto, it has been known that simple epoxides can be opened with amines or ammonia [Eliel: Steric Effects in Organic Chemistry, p. 106 (1956)]. On the basis of this knowledge, Batres et al. have succeeded in the ring opening of 5OL,60c-POXYSt6I'OldS with amines to produce 5c:-hydroxy-Gfi-aminosteroids wherein the amino group is tertiary [Batres et al.: J. Org. Chem, vol. 26, p. 878 (1961)]. The present inventor has attempted to synthesize a steroid having a free amino group and, on the basis of the said knowledge, to react a 5a,6a-epoxysteroid with ammonia. As the result of the attempt, however, only a resinous material has been recovered with no production of the objective amine. By the subsequent study, it has been discovered that a 5a,6a-epoxysteroid is ringopened with hydrogen azide or alkali azide and the resulting 5oc-hydroxy-6B-azidosteroid reduced in a per se conventional procedure to give the 5a-hydroxy-6fi-aminosteroid. The present invention is based on this discovery.

Accordingly, it is a basic object of the present invention to embody a novel route for introducing a free amino group into the 6-position of steroids of the androstane series. Another object of the invention is to embody 5ot-hydroxy-dfl-aminosteroids of the androstane series which are pharmacologically active. A further object of the invention is to embody 5a-hydroxy-6fl-azidosteroids of the androstane series which are intermediates in the said route. Other objects will be apparent to those conversant with the art to which the present invention pertains from the subsequent description.

According to the process of the present invention, the starting 50,6ec-6P0XYSt6IOid of the androstane series is first subjected to epoxy linkage fission by treating the same with hydrogen azide or alkali azide (e.g. sodium azide, potassium azide). The reaction is advantageously carried out in a suitable diluent such as Water, methanol, ethanol, ether, dioxane and tetrahydrofuran or in a mixture of two or more such solvents. The reaction temperature may range, for example, from 80 to 150 C., when the reaction is executed in a sealed tube. The resulting 5 a-hydroxy-6fi-azidosteroid of the androstane series is then subjected to reduction in a per se conventional manner. As the reduction procedure, there may be advantageously adopted a catalytic reduction procedure or a reduction procedure using a reducing agent such as metal hydride. When the reduction procedure using a metal hydride (e.g. lithium aluminum hydride, lithium tritertiary butoxy aluminum hydride) is adopted, the reaction may be carried out by treating the 5a-hydroxy-6B- azidosteroid of the androstane series with the metal hydride in an inert organic solvent such as ether, tetrahydrofuran and dioxane advantageously at a temperature between room temperature to C.) and the boiling temperature of the solvent employed.

The resulting Sa-hydroxy-6,8-aminosteroid of the androstane series may be, if necessary, further converted into the corresponding 5a-hydroxy-B-acylaminosteroid of the androstane series by a conventional acylation pro- 3,156,716 Patented Nov. 10, 1964 ice cedure such as treatment with a lower alkanoic anhydride (e.g. acetic anhydride, propionic anhydride) and an organic base (eg. pyridine, picoline), the latter being sometimes purified more readily than the former.

The thus-produced 5a-hydroxy-6B-aminosteroid of the androstane series and the 6-acylate thereof are useful as CNS (central nervous system) depressing agents. For instance, 365a,17/3-trihydroXy-6fl-aminoandrostane induces anesthetic state in mice, when administered at a non-toxic dose by intraperitoneal route.

The starting 5m,6ot-epoxysteroid of the androstane series may, apart from the substi-tuent at the 5- and 6-positions, contain further substituents, such as free or functionally converted hydroxyl, 0x0 or carboxyl groups, also methyl groups, and it may also contain double bonds. In the course of the reduction step of the present process, free oxo groups may be simultaneously converted into hydroxyl groups and free and functionally converted carboxyl groups into hydroxymethyl groups. If such simultaneous conversion is not favorable, the previous protection of the convertible groups according to a per se conventional manner is required. Specific starting materials are, for example, 17/3-acetoxy-5 DL,6CL-BPOXy3.I1dI'OStfln 3-one S-ethyleneketal [Bowers et al.: Tetrahedron, vol. 7, p. 138 (1959)], 3B,17fi-dihydroxy-17a-methyl-5a,6otepoxyandrostane 3,17-diacetate [Julia et al.: Helv. Chim. Aota, vol 35, p. 2080 (1952)], methyl 3B-acetoxy-5a,6otepoxyandrostan-17B-carboxylate [Heusser et al.: Helv. Chim. Acta, vol. 32, p. 1334 (1949)], 3,B-acetoxy-5a,6tzepoxyandrostan-17-one, 3B,17fi-dihydroxy-5a,6m-epoxyandrostane 3,17-diacetate [Ringold et al.: J. Org. Chem, vol. 22, p. 99 (1957)], etc.

The following examples illustrate presently-preferred embodiments of the invention. In these examples, abbreviations each has the conventional meaning, e.g. mg.=milligram(s), g.=grarn(s), ml.=milliliter(s),

Example 1 C.=degrees Centigrade.

OH OH (H1 OOOCHs I (13 (I l I ..Q@ .....Q@

no NEE no Nnooom (A) Preparation of 3fi,5u,17,8-trihydr0xy-6fi-azidoandrostrane. A solution of 3B,17,8-dihydroXy-5u,6ot-epoxyandrostane [Wada: Yakugaku Zasshi, Vol. 79, p. 684 (1959)] (0.98 g.) in ethanol (8 ml.) is combined with a solution of sodium azide (0.5 g.) in water (1.5 ml.), and the resulting mixture is heated in a sealed tube for 32 hours at C; The reaction mixture is concentrated under reduced pressure. The condensate is combined with water and shaken with ether. The ether phase is washed with water, dried over anhydrous sodium sulfate and evapo rated. The residue is crystallized from a mixture of methanol and ether to give 3,8,5,17,8-trihydroxy-65-azi- 53 doandrostane (0.95 g.) as crystals melting at 197.5 to 199 C.

(B) Preparation of 3/3,5ct,1 7B-tr1'lzydr0xy-6p-aminoaltdrstalze.A solution of 3/3504,17,3-trihydroxy-6fi-azidoandrostane (100 mg.) in anhydrous tetrahydrofuran (5 ml.) and a solution of lithium aluminum hydride (100 mg.) in anhydrous other (3 ml.) are combined together, and the resulting mixture is refluxed for 3.5 hours on a water bath. Excess of the reducing agent is decomposed with Water. The reaction mixture is concentrated under reduced pressure. The residue is extracted with anhydrous ethanol. The ethanol extract is evaporated and crystallized from a mixture of methanol and ether to give 3,8,5a, 17,6-trihydroxy-6fi-aminoandrostane (50 mg.) as crystals melting at 246 to 249 C. (decomp).

(C) Preparation of 3B,5a,I7,8-trilzydroxy-tfifi-acetylaminoana'rostane 3,1 7-diacefate.A mixture of 3fi,5a,l7fltrihydroxy-6,8-aminoandrostane mg.) in pyridine (0.5 ml.) and acetic anhydride (0.5 ml.) is stirred for 16 hours at room temperature (15 to C.). The reaction mixture is concentrated under reduced pressure. The residue is combined with water and shaken with ether. The ether phase is Washed with dilute hydrochloric acid and then dilute aqueous solution of sodium carbonate, dried over anhydrous sodium sulfate and evaporated. The residue is crystallized from a mixture or" acetone and hexane to give 3/115,175-trihydroxy-6fl-acetylaminoandrostane 3,17-diacetate (12 mg.) as crystals melting at 271 to 273.5 C.

Analysis.-Calcd. for C H O N: C, 66.79; H, 8.75;

N, 3.12. Found: c, 66.31; H, 8.99; N, 3.05.

Example 2 OCOCH;

as w o no N3 tallized from a mixture of acetone and hexane to give 355a,l7,8-trihydroxy-6fi-azidoandrostane 3,17 diacetate (1.00 g.) as crystals melting at 180 to l81.5 C.

Analysis.Calcd. for C H O N C, 63.72; H, 8.14; N, 9.69. Found: C, 63.55; H, 8.23; N, 9.52.

(B) Preparation of 395a,]7fl-trihydr0xy-6fl-amin0andr0stane.3 5,5a,l7fi trihydroxy 65 azidoandrostane 3,17-diacetate (1.00 mg.) is subjected to reduction with lithium aluminum hydride as in Example 1 (B) whereby 3/351,17,8-trihydroxy-6fi-aminoandrostane (92 mg.) is produced.

Example 3 i l L] u l L.

0: I-IO- v, no N; no Nm (A) Preparation of Sa-hy(1r0xy-6/3-azidoana'roslane- 3,]7-di0ne.5o,6a epoxyandrostane-3,l7-dione [Campbell et al.: J. Am. Chem. Soc., vol. 80, p. 471.7 (1958)] (1.00 g.) is subjected to reaction with sodium azide as in Example 1 (A) whereby Six-hydroxy-6,8-azidoandrostane- 3,17-dione (0.84 g.) is produced. Recrystallization of the product from a mixture of acetone and hexane gives crystals melting at 231 to 232 C. (decomp).

AnaIysis.-Calcd. for C l-l O N C, 66.06; H, 7.88; N, 12.17. Found: C, 65.95; H, 8.05; N, 12.40.

(B) Preparation of 5fi,5a,17fl-tri/zydr0xy-6B-amin0andr0szane.5u hydroxy 6/) azidoandr0stane-3,l7-dione (500 mg.) is subjected to reduction with lithium aluminum hydride as in Example 1 (B) whereby 35,504,178- trihydroxy-6B-aminoandrostane (410 mg.) is produced.

What is claimed is:

1. 3,8,5a,17/3-trihydroxy-6fi-azidoandrostane.

2. 3,8,5a,17,8-tril1ydroxy 6d azidoandrostane 3,17-diacetate.

3. 5a-hydroxy-6fl-azidoandrostame-3,l7-dione.

4. 3,8,5,l-trihydroxy-6B-aminoandrostane.

5. 3fi,5 x,17,8 trihydroxy 6,8 acetylaminoandrostane 3,17-diacetate.

OTHER REFERENCES Boyer et al.: Alkyl and Aryl Azides, Chemical Reviews, v01. 54, No. 1, February 1954, p. 10. 

1. 3B, 5A, 17B-TRIHYDROXY-6B-AZIDOANDROSTANE. 